1. Field of the Invention
This invention is directed to compounds that provide for the enhanced and prolonged systemic blood concentrations of drugs that are incompletely translocated across the intestinal wall after oral delivery to animals. This invention is also directed to pharmaceutical compositions containing and methods using such compounds.
2. State of the Art
Incomplete or poor oral bioavailability of both existing and developmental stage therapeutic and/or prophylactic compounds represents a major impediment to effective pharmaceutical drug development. Though multiple factors influence the bioavailability of drugs (including solubility, dissolution rate, first-pass metabolism, p-glycoprotein and related efflux mechanisms, etc), low intestinal cell permeability is a particularly significant reason for the poor systemic absorption of many compounds.
Compound uptake from the gut is significantly curtailed by the network of tight junctions formed by the intestinal epithelial cell layer, and the majority of drugs that are orally absorbed traverse this epithelial barrier by passive diffusion across the apical and basolateral membranes of these cells.
The physicochemical features of a molecule that favor its passive uptake from the intestinal lumen into the systemic circulation include low molecular weight (e.g. <500 Da), adequate solubility, and a balance of hydrophobic and hydrophilic character (logP generally 1.5-4.0) (Navia and Chaturvedi, 1996). Polar or hydrophilic compounds are typically poorly absorbed through an animal's intestine as there is a substantial energetic penalty for passage of such compounds across the lipid bilayers that constitute cellular membranes. Many nutrients that result from the digestion of ingested foodstuffs in animals, such as amino acids, di- and tripeptides, monosaccharides, nucleosides and water-soluble vitamins, are polar compounds whose uptake is essential to the viability of the animal. For these substances there exist specific mechanisms for active transport of the solute molecules across the apical membrane of the intestinal epithelia. This transport is frequently energized by co-transport of ions down a concentration gradient. Solute transporter proteins are generally single sub-unit, multi-transmembrane spanning polypeptides, and upon binding of their substrates are believed to undergo conformational changes which result in movement of the substrate(s) across the membrane.
Over the past 10-15 years, it has been found that a number of orally administered drugs are recognized as substrates by some of these transporter proteins, and that this active transport may largely account for the oral absorption of these molecules (Tsuji and Tamai, 1996). While in most instances the transporter substrate properties of these drugs were unanticipated discoveries made through retrospective analysis, it has been appreciated that, in principle, one might achieve good intestinal permeability for a drug by designing in recognition and uptake by a nutrient transport system.
Incomplete bioavailability of drugs that, nevertheless, are orally delivered necessitates the administration of a larger dose of such drug to compensate for that amount of drug not delivered to the systemic blood circulation. Such larger doses of the drug, however, may result in greater variability in drug exposure, more frequent occurrence of side effects, decrease in patient compliance, or alternatively, require use of parenteral delivery routes.
One attractive pathway that might be exploitable for oral delivery of such drugs is the intestinal bile acid transport system (Swaan et al, 1996). Bile acids are hydroxylated steroids that play a key role in digestion and absorption of fat and lipophilic vitamins. After synthesis in the liver, they are secreted into bile and excreted by the gall bladder into the intestinal lumen where they emulsify and help solubilize lipophilic substances. Bile acids are conserved in the body by active uptake from the terminal ileum via the sodium-dependent transporter IBAT (or ASBT) and subsequent hepatic extraction by the transporter NTCP located in the sinusoidal membrane of hepatocytes. This efficient mechanism to preserve the bile acid pool is termed the enterohepatic circulation (see FIG. 1). In man, the total bile acid pool (3-5 g) recirculates 6-10 times per day giving rise to a daily uptake of approximately 20-30 g of bile acids.
The high transport capacity of the bile acid pathway has been a key reason for interest in this system for drug delivery purposes. Several papers have postulated that chemical conjugates of bile acids with drugs could be used to provide liver site-directed delivery of a drug to bring about high therapeutic concentrations in the diseased liver with minimization of general toxic reactions elsewhere in the body; and gallbladder-site delivery systems of cholecystographic agents and cholesterol gallstone dissolution accelerators” (Ho, 1987). Several groups have explored these concepts in some detail, using the C-24 carboxylic acid, C-3, C-7, and C-12 hydroxyl groups of cholic acid (and other bile acids) as handles for chemically conjugating drugs or drug surrogates. (Kramer, et al., 1992, Kim, et al., 1993).
The most rigorous drug targeting studies using the bile acid transport pathway to date relate to work with bile acid conjugates of HMG-CoA reductase inhibitors (Kramer et al, 1994b; Petzinger et al, 1995; Kramer and Wess, 1995; Kramer et al, 1997b). Coupling of the HMG-CoA reductase inhibitor HR 780 via an amide linkage to the C-3 position of cholate, taurocholate and glycocholate afforded substrates for both the ileal and liver bile acid transporter proteins (FIG. 2). Upon oral dosing of rats, the cholate conjugate S 3554 led to specific inhibition of HMG-CoA reductase in the liver, and in contrast to the parent compound HR 780, gave significantly reduced inhibition of the enzyme in extra-hepatic organs. Companion studies that looked at the tissue distribution of radiolabeled drugs two hours after i.v., administration through the mesenteric vein of rats also showed dramatically lower systemic levels for the bile acid conjugate relative to the parent. Because inhibition of HMG-CoA reductase requires the presence of the free carboxylic acid moiety in HR 780 this data was taken to indicate that S 3554 served as a prodrug of HR 780, undergoing hydrolysis (and other uncharacterized metabolism) in the rat liver. Interestingly, uptake of S 3554 by liver did not appear to depend on the liver bile acid transporter NTCP (which prefers taurocholate conjugates), but may instead have involved another multispecific organic anion transport system on the sinusoidal hepatocyte membrane.
Syntheses of substituted steroids are well known in the art. By way of example, hetercyclic derivatives of 3,7,12-triketo-cholanic acid, including diaminopyriidine, diamino-, and diketopteridine derivatives, in which the heterorings are fused to both the A and B rings of steroidic compounds in positions 2, 3 and 6, 7 or 3, 4 and 6, 7, are known. (Bellini et al, 1969; Bellini et al; Rocchi et al). In addition, heterosteroids containing a dihydroethisterone skeleton have been prepared and have been shown to displace substance P in receptor binding assays. (Venepalli et al, 1992).
In summary, while the concept of harnessing the intestinal bile acid uptake pathway to enhance the absorption of poorly absorbed drugs is well appreciated, the existing art has merely demonstrated that bile acid-drug conjugates may be effectively trafficked to the liver and generally excreted into the bile, either unchanged or as some type of metabolite. The art gives no guidance as to how one prepares a composition that exploits the bile acid transport pathway and simultaneously provides therapeutically meaningful levels of a drug substance outside of the enterohepatic circulation. The art further gives no guidance as to bile acid derivatives that can be used in such a composition.